DESCRIPTION (Adapted from the application): More than one-third of Americans are overweight (obese), and it is important to identify new therapeutic treatments for this condition. A number of approaches include liquid diets, calorie counting, fat counting, commercial weight loss programs, and the use of drugs. In the 1960's and 1970's amphetamines were the drug of choice, but they caused many problems including addiction. In the 1990's, fenfluramine and phentermine are used to reduce the appetite. However, there are some major concerns about the use of these drugs and the effects on serotonin centers. The objective of this proposal is to design, synthesize, characterize, and test tetrahydroisoquinoline analogs for their ability to break down fat through the selective activation of beta(3)-adrenoceptors. Dr. Miller will synthesize the designed molecules at the University of Tennessee. Dr. Purcell from MDI will work with us using the QSAR CoMFA program to optimize the structures for activation of beta(3)-adrenergic receptors and Dr. Feller, at the University of Mississippi, will test the compounds for the binding and activation of the three subtypes of human beta-adrenergic receptors. Selective beta(3)-adrenergic drugs will be useful for the treatment of obesity and non insulin dependent diabetes mellitus. PROPOSED COMMERCIAL APPLICATION: A drug that is effective and safe for the treatment of obesity will have significant commercial success.